The role of donor‐unrestricted T‐cells, innate lymphoid cells, and NK cells in anti‐mycobacterial immunity

Vaccination strategies against mycobacteria, focusing mostly on classical T‐ and B‐cells, have shown limited success, encouraging the addition of alternative targets. Classically restricted T‐cells recognize antigens presented via highly polymorphic HLA class Ia and class II molecules, while donor‐unrestricted T‐cells (DURTs), with few exceptions, recognize ligands via genetically conserved antigen presentation molecules. Consequently, DURTs can respond to the same ligands across diverse human populations. DURTs can be activated either through cognate TCR ligation or via bystander cytokine signaling. TCR‐driven antigen‐specific activation of DURTs occurs upon antigen presentation via non‐polymorphic molecules such as HLA‐E, CD1, MR1, and butyrophilin, leading to the activation of HLA‐E–restricted T‐cells, CD1‐restricted T‐cells, mucosal‐associated invariant T‐cells (MAITs), and TCRγδ T‐cells, respectively. NK cells and innate lymphoid cells (ILCs), which lack rearranged TCRs, are activated through other receptor‐triggering pathways, or can be engaged through bystander cytokines, produced, for example, by activated antigen‐specific T‐cells or phagocytes. NK cells can also develop trained immune memory and thus could represent cells of interest to mobilize by novel vaccines. In this review, we summarize the latest findings regarding the contributions of DURTs, NK cells, and ILCs in anti–M tuberculosis, M leprae, and non‐tuberculous mycobacterial immunity and explore possible ways in which they could be harnessed through vaccines and immunotherapies to improve protection against Mtb.